tbuckley/cabot-search huggingface dataset:
Comparative Genomics of the Waterfowl Innate Immune System
Authors: Elinor Jax, Paolo Franchini, Vaishnovi Sekar, Jente Ottenburghs, Daniel Monné Parera, Roman T Kellenberger, Katharine E Magor, Inge Müller, Martin Wikelski, Robert H S Kraus
Journal: Molecular Biology and Evolution (2022)

Abstract Animal species differ considerably in their ability to fight off infections. Finding the genetic basis of these differences is not easy, as the immune response is comprised of a complex network of proteins that interact with one another to defend the body against infection. Here, we used population- and comparative genomics to study the evolutionary forces acting on the innate immune system in natural hosts of the avian influenza virus (AIV). For this purpose, we used a combination of hybrid capture, next- generation sequencing and published genomes to examine genetic diversity, divergence, and signatures of selection in 127 innate immune genes at a micro- and macroevolutionary time scale in 26 species of waterfowl. We show across multiple immune pathways (AIV-, toll-like-, and RIG-I -like receptors signalling pathways) that genes involved genes in pathogen detection (i.e., toll-like receptors) and direct pathogen inhibition (i.e., antimicrobial peptides and interferon-stimulated genes), as well as host proteins targeted by viral antagonist proteins (i.e., mitochondrial antiviral-signaling protein, [MAVS]) are more likely to be polymorphic, genetically divergent, and under positive selection than other innate immune genes. Our results demonstrate that selective forces vary across innate immune signaling signalling pathways in waterfowl, and we present candidate genes that may contribute to differences in susceptibility and resistance to infectious diseases in wild birds, and that may be manipulated by viruses. Our findings improve our understanding of the interplay between host genetics and pathogens, and offer the opportunity for new insights into pathogenesis and potential drug targets.
GMC: harsh punishment is a sword of Damocles
Authors: Santhanam Sundar
Journal: BMJ (2022)

<h3>Practical Applications Summary</h3> In <b>“Flexicure” Retirement Solutions: <i>A Part of the Answer to the Pension Crisis?</i></b>, from the July 2019 issue of <b><i>The Journal of Portfolio Management</i></b>, authors <b>Lionel Martellini</b> (of <b>EDHEC-Risk Institute</b>), <b>Vincent Milhau</b> (of <b>EDHEC-Risk Institute</b>), and <b>John Mulvey</b> (of <b>Princeton University</b>) introduce a range of goal-based retirement investing strategies that allow for both security and flexibility. They describe such strategies as “flexicure,” a portmanteau of “flexible” and “secure.” The authors also describe how combining bonds, annuities, and equities can lead to improvements in the use of existing multi-asset products for retirement investing. They explain how to apply principles of goal-based investing in the retirement context and highlight the benefits of their strategies. <b>TOPICS:</b>Retirement, portfolio construction, quantitative methods
Surface Lin28A expression consistent with cellular stress parallels indicators of senescence
Authors: Kathleen Broughton, Carolina Esquer, Oscar Echeagaray, Fareheh Firouzi, Grant Shain, David Ebeid, Megan Monsanto, Dena Yaareb, Leila Golgolab, Natalie Gude, Mark A Sussman
Journal: Cardiovascular Research (2022)

Abstract Aims Declining cellular functional capacity resulting from stress or ageing is a primary contributor to impairment of myocardial performance. Molecular pathway regulation of biological processes in cardiac interstitial cells (CICs) is pivotal in stress and ageing responses. Altered localization of the RNA-binding protein Lin28A has been reported in response to environmental stress, but the role of Lin28A in response to stress in CICs has not been explored. Surface Lin28A redistribution is indicative of stress response in CIC associated with ageing and senescence. Methods and results Localization of Lin28A was assessed by multiple experimental analyses and treatment conditions and correlated to oxidative stress, senescence, and ploidy in adult murine CICs. Surface Lin28A expression is present on 5% of fresh CICs and maintained through Passage 2, increasing to 21% in hyperoxic conditions but lowered to 14% in physiologic normoxia. Surface Lin28A is coincident with elevated senescence marker p16 and beta-galactosidase (β-gal) expression in CICs expanded in hyperoxia, and also increases with polyploidization and binucleation of CICs regardless of oxygen culture. Transcriptional profiling of CICs using single-cell RNA-Seq reveals up-regulation of pathways associated with oxidative stress in CICs exhibiting surface Lin28A. Induction of surface Lin28A by oxidative stress is blunted by treatment of cells with the antioxidant Trolox in a dose-dependent manner, with 300 μM Trolox exposure maintaining characteristics of freshly isolated CICs possessing low expression of surface Lin28A and β-gal with predominantly diploid content. Conclusion Surface Lin28A is a marker of environmental oxidative stress in CICs and antioxidant treatment antagonizes this phenotype. The biological significance of Lin28 surface expression and consequences for myocardial responses may provide important insights regarding mitigation of cardiac stress and ageing.
Partha Kar: NHS restructuring—can our leaders make it work?
Authors: Partha Kar
Journal: BMJ (2022)

<b>Background:</b> Segawa syndrome due to GTP cyclohydrolase deficiency is an autosomal dominant disorder with variable expression, that is clinically characterised by l-dopa responsive, diurnally fluctuating dystonia and parkinsonian symptoms. <b>Objective:</b> To delineate the neurological and psychiatric phenotype in all affected individuals of three extended families. <b>Methods:</b> GTP cyclohydrolase deficiency was documented by biochemical analyses, enzymatic measurements in fibroblasts, and molecular investigations. All affected individuals were examined neurologically, and psychiatric data were systematically reviewed. <b>Results:</b> Eighteen affected patients from three families with proven GTP cyclohydrolase deficiency were identified. Eight patients presenting at less than 20 years of age had typical motor symptoms of dystonia with diurnal variation. Five family members had late-presenting mild dopa-responsive symptoms of rigidity, frequent falls, and tendonitis. Among mutation carriers older than 20 years of age, major depressive disorder, often recurrent, and obsessive-compulsive disorder were strikingly more frequent than observed in the general population. Patients responded well to medication increasing serotonergic neurotransmission and to l-dopa substitution. Sleep disorders including difficulty in sleep onset and maintenance, excessive sleepiness, and frequent disturbing nightmares were present in 55% of patients. <b>Conclusion:</b> Physicians should be aware of this expanded phenotype in affected members of families with GTP cyclohydrolase deficiency.
Why I . . . pole dance
Authors: Kathy Oxtoby
Journal: BMJ (2022)

<h3>Abstract</h3> Dimensionality reduction is standard practice for filtering noise and identifying relevant dimensions in large-scale data analyses. In biology, single-cell expression studies almost always begin with reduction to two or three dimensions to produce ‘all-in-one’ visuals of the data that are amenable to the human eye, and these are subsequently used for qualitative and quantitative analysis of cell relationships. However, there is little theoretical support for this practice. We examine the theoretical and practical implications of low-dimensional embedding of single-cell data, and find extensive distortions incurred on the global and local properties of biological patterns relative to the high-dimensional, ambient space. In lieu of this, we propose semi-supervised dimension reduction to higher dimension, and show that such <i>targeted</i> reduction guided by the metadata associated with single-cell experiments provides useful latent space representations for hypothesis-driven biological discovery.
Isolation facilities for covid-19: towards a person centred approach
Authors: Chuan De Foo, Victoria Haldane, Anne-Sophie Jung, Karen A Grépin, Shishi Wu, Sudhvir Singh, Niranjala Perera, J Jaime Miranda, Martin McKee, Helena Legido-Quigley
Journal: BMJ (2022)

<b>Chuan De Foo and colleagues</b> argue that isolation facilities have the potential to interrupt the transmission of infectious agents, particularly in the earlier stages of infectious disease outbreaks, but they must deliver person centred care
Comparing IADPSG and NICE Diagnostic Criteria for GDM in Predicting Adverse Pregnancy Outcomes
Authors: Yuanying He, Ronald Ching Wan Ma, H. David McIntyre, David A. Sacks, Julia Lowe, Patrick M. Catalano, Wing Hung Tam
Journal: Diabetes Care (2022)

To compare the performance of diagnostic criteria for gestational diabetes mellitus (GDM) proposed by the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) with those endorsed by the National Institute for Health and Care Excellence (NICE) in predicting adverse pregnancy outcomes.We performed a secondary data analysis of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study participants in five study centers. Logistic regression analyses were performed, and Akaike information criterion were applied for the comparison of different statistical prediction models. We further analyzed the performance by four racial/ethnic subgroups, namely, Whites, Hispanics, Asians, and Blacks.Among all, IADPSG criteria diagnosed 267 (4.1%) more women with GDM, but predicted primary caesarean section (CS) and large for gestational age (LGA) and neonatal adiposity better than did NICE criteria after adjustment for potential confounders. Among Whites, IADPSG criteria diagnosed 65 (2.5%) more subjects with GDM and predicted LGA and neonatal adiposity better, but predicted hypertensive disorders, primary CS and clinical neonatal hypoglycemia worse. Among Hispanics, the IADPSG criteria diagnosed 203 (12.1%) more with GDM but performed better in predicting hypertensive disorders, LGA, neonatal adiposity, and hyperinsulinemia. Among Asians, the IADPSG criteria diagnosed 34 (2.0%) fewer subjects with GDM but predicted hypertensive disorders better in the unadjusted model. In Blacks, IADPSG criteria diagnosed 34 (10.5%) more women with GDM.IADPSG criteria appear to be more favorable than NICE for identification of adverse pregnancy outcomes among Hispanic and Asian women, while they are comparable to NICE among White women.
Lifestyle Intervention Strategy to Treat Diabetes in Older Adults: A Randomized Controlled Trial
Authors: Alessandra Celli, Yoann Barnouin, Bryan Jiang, Dean Blevins, Georgia Colleluori, Sanjay Mediwala, Reina Armamento-Villareal, Clifford Qualls, Dennis T. Villareal
Journal: Diabetes Care (2022)

Lifestyle intervention is recommended as first-line treatment of diabetes at all ages; however, little is known about the efficacy of lifestyle intervention in older adults with diabetes. We aimed to determine whether lifestyle intervention would improve glycemic control and age-relevant outcomes in older adults with diabetes and comorbidities.A total of 100 older adults with diabetes were randomly assigned to 1-year intensive lifestyle intervention (ILI) (diet and exercise at a facility transitioned into community-fitness centers and homes) or healthy lifestyle (HL) group. The primary outcome was change in HbA1c. Secondary outcomes included glucoregulation, body composition, physical function, and quality of life. Changes between groups were analyzed with mixed-model repeated-measures ANCOVA following the intention-to-treat principle.HbA1c improved more in the ILI than the HL group (mean ± SE -0.8 ± 0.1 vs. 0.1 ± 0.1%), associated with improved insulin sensitivity (1.2 ± 0.2 vs. -0.4 ± 0.2) and disposition (26.0 ± 8.9 vs. -13.0 ± 8.4 109 min-1) indices (between-group P < 0.001 to 0.04). Body weight and visceral fat decreased more in the ILI than HL group (-8.4 ± 0.6 vs. -0.3 ± 0.6 kg, P < 0.001, and -261 ± 29 vs. -30 ± 27 cm3, P < 0.001, respectively). Physical Performance Test score increased more in the ILI than HL group (2.9 ± 0.6 vs. -0.1 ± 0.4, P < 0.001) as did VO2peak (2.2 ± 0.3 vs. -1.2 ± 0.2 mL/kg/min, P < 0.001). Strength, gait, and 36-Item Short Form Survey (SF-36) Physical Component Summary score also improved more in the ILI group (all P < 0.001). Total insulin dose decreased in the ILI group by 19.8 ± 4.4 units/day. Adverse events included increased episodes of mild hypoglycemia in the ILI group.A lifestyle intervention strategy is highly successful in improving metabolic and functional health of older adults with diabetes.
Temporal changes in paediatric and adolescent HIV outcomes across the care continuum in Zambia: an interrupted time-series analysis
Authors: Carolyn Bolton-Moore, Izukanji Sikazwe, Mwangelwa Mubiana-Mbewe, Gloria Munthali, Mwanza wa Mwanza, Theodora Savory, Lugano Nkhoma, Paul Somwe, Angella Sandra Namwase, Elvin H Geng, Aaloke Mody
Journal: The Lancet HIV (2022)
Effects of Dapagliflozin According to the Heart Failure Collaboratory Medical Therapy Score
Authors: Jawad H. Butt, Pooja Dewan, Ersilia M. DeFilippis, Tor Biering-Sørensen, Kieran F. Docherty, Pardeep S. Jhund, Mikhail N. Kosiborod, Felipe A. Martinez, Olof Bengtsson, Niklas Dyrby Johansen, Anna Maria Langkilde, Mikaela Sjöstrand, Muthiah Vaduganathan, Scott D. Solomon, Marc S. Sabatine, Lars Køber, Mona Fiuzat, John J.V. McMurray
Journal: JACC Heart Failure (2022)
Sodium-Glucose Co-Transporter-2 Inhibitors and Cardiac Outcomes Among Patients Treated With Anthracyclines
Authors: Carlos A Gongora, Zsofia D Drobni, Thiago Quinaglia Araujo Costa Silva, Amna Zafar, Jingyi Gong, Daniel A Zlotoff, Hannah K Gilman, Sarah E Hartmann, Supraja Sama, Sofia Nikolaidou, Giselle Alexandra Suero-Abreu, Eric Jacobsen, Jeremy S Abramson, Ephraim Hochberg, Jeffrey Barnes, Philippe Armand, Paaladinesh Thavendiranathan, Anju Nohria, Tomas G Neilan
Journal: JACC Heart Failure (2022)
The first-in-class ERK inhibitor ulixertinib shows promising activity in mitogen-activated protein kinase (MAPK)-driven pediatric low-grade glioma models
Authors: Romain Sigaud, Lisa Rösch, Charlotte Gatzweiler, Julia Benzel, Laura von Soosten, Heike Peterziel, Florian Selt, Sara Najafi, Simay Ayhan, Xenia F Gerloff, Nina Hofmann, Isabel Büdenbender, Lukas Schmitt, Kathrin I Foerster, Jürgen Burhenne, Walter E Haefeli, Andrey Korshunov, Felix Sahm, Cornelis M van Tilburg, David T W Jones, Stefan M Pfister, Deborah Knoerzer, Brent L Kreider, Max Sauter, Kristian W Pajtler, Marc Zuckermann, Ina Oehme, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2022)

Abstract Background Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors. Methods We investigated the antitumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549:BRAF-fusion and BRAFV600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing. Results Ulixertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of antiproliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival. Conclusions These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned international phase I/II umbrella trial.
Update on pathomechanisms and treatments in allergic rhinitis
Authors: Yuan Zhang, Feng Lan, Luo Zhang
Journal: Allergy (2022)

Abstract Allergic rhinitis (AR) is a global health problem with increasing prevalence and association with an enormous medical and socioeconomic burden. New recognition of immune cells such as type 2 innate lymphocytes (ILC2s), T helper (Th2) 2 cells, follicular helper T cells, follicular regulatory T cells, regulatory T cells, B cells, dendritic cells, and epithelial cells in AR pathogenesis has been updated in this review paper. An in‐depth understanding of the mechanisms underlying AR will aid the identification of biomarkers associated with disease and ultimately provide valuable parameters critical to guide personalized targeted therapy. As the only etiological treatment option for AR, allergen‐specific immunotherapy (AIT) has attracted increasing attention, with evidence for effectiveness of AIT recently demonstrated in several randomized controlled trials and long‐term real‐life studies. The exploration of biologics as therapeutic options has only involved anti‐IgE and anti‐type 2 inflammatory agents; however, the cost‐effectiveness of these agents remains to be elucidated precisely. In the midst of the currently on‐going COVID‐19 pandemic, a global life‐threatening disease, although some studies have indicated that AR is not a risk factor for severity and mortality of COVID‐19, this needs to be confirmed in multi‐centre, real‐life studies of AR patients from different parts of the world.
Immunomodulation by foods and microbes: Unravelling the molecular tango
Authors: Brian Forde, Lu Yao, Rupin Shaha, Sally Murphy, Nonhlanhla Lunjani, Liam O'Mahony
Journal: Allergy (2022)

Metabolic health and immune function are intimately connected via diet and the microbiota. Nearly 90% of all immune cells in the body are associated with the gastrointestinal tract and these immune cells are continuously exposed to a wide range of microbes and microbial-derived compounds, with important systemic ramifications. Microbial dysbiosis has consistently been observed in patients with atopic dermatitis, food allergy and asthma and the molecular mechanisms linking changes in microbial populations with disease risk and disease endotypes are being intensively investigated. The discovery of novel bacterial metabolites that impact immune function is at the forefront of host-microbe research. Co-evolution of microbial communities within their hosts has resulted in intertwined metabolic pathways that affect physiological and pathological processes. However, recent dietary and lifestyle changes are thought to negatively influence interactions between microbes and their host. This review provides an overview of some of the critical metabolite-receptor interactions that have been recently described, which may underpin the immunomodulatory effects of the microbiota, and are of relevance for allergy, asthma and infectious diseases.
Molecular stratification of arrhythmogenic mechanisms in the Andersen Tawil syndrome
Authors: Ana Isabel Moreno-Manuel, Lilian K Gutiérrez, María Linarejos Vera-Pedrosa, Francisco Miguel Cruz, Francisco José Bermúdez-Jiménez, Isabel Martínez-Carrascoso, Patricia Sánchez-Pérez, Álvaro Macías, José Jalife
Journal: Cardiovascular Research (2022)

Andersen-Tawil syndrome (ATS) is a rare inheritable disease associated with loss-of-function mutations in KCNJ2, the gene coding the strong inward rectifier potassium channel Kir2.1, which forms an essential membrane protein controlling cardiac excitability. ATS is usually marked by a triad of periodic paralysis, life-threatening cardiac arrhythmias and dysmorphic features, but its expression is variable and not all patients with a phenotype linked to ATS have a known genetic alteration. The mechanisms underlying this arrhythmogenic syndrome are poorly understood. Knowing such mechanisms would be essential to distinguish ATS from other channelopathies with overlapping phenotypes and to develop individualized therapies. For example, the recently suggested role of Kir2.1 as a countercurrent to sarcoplasmic calcium reuptake might explain the arrhythmogenic mechanisms of ATS and its overlap with catecholaminergic polymorphic ventricular tachycardia. Here we summarize current knowledge on the mechanisms of arrhythmias leading to sudden cardiac death in ATS. We first provide an overview of the syndrome and its pathophysiology, from the patient's bedside to the protein and discuss the role of essential regulators and interactors that could play a role in cases of ATS. The review highlights novel ideas related to some post-translational channel interactions with partner proteins that might help define the molecular bases of the arrhythmia phenotype. We then propose a new all-embracing classification of the currently known ATS loss-of-function mutations according to their position in the Kir2.1 channel structure and their functional implications. We also discuss specific ATS pathogenic variants, their clinical manifestations, and treatment stratification. The goal is to provide a deeper mechanistic understanding of the syndrome toward the development of novel targets and personalized treatment strategies.
Gut Microbially Produced Indole-3-Propionic Acid Inhibits Atherosclerosis by Promoting Reverse Cholesterol Transport and Its Deficiency Is Causally Related to Atherosclerotic Cardiovascular Disease
Authors: Hongliang Xue, Xu Chen, Chao Yu, Yuqing Deng, Yuan Zhang, Shen Chen, Xuechen Chen, Ke Chen, Yan Yang, Wenhua Ling
Journal: Circulation Research (2022)

Background: Accumulating evidence has shown that disorders in the gut microbiota and derived metabolites affect the development of atherosclerotic cardiovascular disease (ASCVD). However, which and how specific gut microbial metabolites contribute to the progression of atherosclerosis and the clinical relevance of their alterations remain unclear. Methods: We performed integrated microbiome–metabolome analysis of 30 patients with coronary artery disease (CAD) and 30 age- and sex-matched healthy controls to identify CAD-associated microbial metabolites, which were then assessed in an independent population of patients with ASCVD and controls (n=256). We further investigate the effect of CAD-associated microbial metabolites on atherosclerosis and the mechanisms of the action. Results: Indole-3-propionic acid (IPA), a solely microbially derived tryptophan metabolite, was the most downregulated metabolite in patients with CAD. Circulating IPA was then shown in an independent population to be associated with risk of prevalent ASCVD and correlated with the ASCVD severity. Dietary IPA supplementation alleviates atherosclerotic plaque development in ApoE −/− mice. In murine- and human-derived macrophages, administration of IPA promoted cholesterol efflux from macrophages to ApoA-I through an undescribed miR-142-5p/ABCA1 (ATP-binding cassette transporter A1) signaling pathway. Further in vivo studies demonstrated that IPA facilitates macrophage reverse cholesterol transport, correlating with the regulation of miR-142-5p/ABCA1 pathway, whereas reduced IPA production contributed to the aberrant overexpression of miR-142-5p in macrophages and accelerated the progression of atherosclerosis. Moreover, the miR-142-5p/ABCA1/reverse cholesterol transport axis in macrophages were dysregulated in patients with CAD, and correlated with the changes in circulating IPA levels. Conclusions: Our study identify a previously unknown link between specific gut microbiota-derived tryptophan metabolite and ASCVD. The microbial metabolite IPA/miR-142-5p/ABCA1 pathway may represent a promising therapeutic target for ASCVD.